New 11 beta-halo-7 alpha-substituted estratrienes useful for treating e.g. estrogen-dependent disease such as breast cancer

摘要

11 beta -Halo-7 alpha -substituted estratrienes (I) are new. Estratriene derivatives of formula (I) are new. R3 = H, 1-8C hydrocarbyl or R'3CO-; R'3 = H, 1-8C hydrocarbyl or Ph; R7 = -A-B-Z-R20; A = direct bond, benzylidene (with the methylene group bonded to the 7-C of the steroid) or phenylene; B = alkylene, alkenylene or alkynylene of 3-14C; (i) Z = NR21; R21 = 1-3C alkyl; and R20 = H; alkyl, alkenyl or alkynyl of up to 20C; -D-Rf; -L-CH=F-R'f; -D-O-(CH2)q-Ar; or -D-O-(CH2)r-Rf; or NR20R21 = optionally substituted 5- or 6-membered, saturated or unsaturated heterocycle, optionally containing 1 or 2 further N, O or S heteroatom(s); (ii) Z = S(O)x; and R20 = as in (i) with the exception of H; or (iii) Z = NR31; and R20 = alkyl, alkenyl or alkynyl of up to 14C (optionally interrupted by 1-3 of O, S and NR32 and optionally partially fluorinated); aryl, heteroaryl, 3-10C cycloalkyl, 4-15C cycloalkylalkyl, 7-20C aralkyl or heteroaryl-(1-6C) alkyl (all optionally mono- or disubstituted); or optionally subsituted aminoalkyl; D = alkylene, alkenylene or alkynylene of up to 8C; Rf = 1-8C perfluoroalkyl; L = alkylene, alkenylene or alkynylene of 2-7C; R'f = 2-7C perfluoroalkyl; q = 0-3; Ar = phenyl, 1- or 2-naphthyl or heteroaryl (both optionally mono- or disubstituted); r = 1-5; R31 = COR33 or CH2R33; R32 = H or 1-3C alkyl; R33 = as R20 in (iii); or biphenylene; R11 = F or Cl; R17 = H or R'17CO-; R'17 = H or 1-8C hydrocarbyl; the following compounds are excluded: 7 alpha -(5-((2S or 2R)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl)-pentyl) -estra-1,3,5(10)-triene-3,17 beta -diol, 11 beta -fluoro-7 alpha -(5-(N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino)-penty l)-3-hydroxy-estra-1,3,5(10)-trien-17-one and 11 beta -fluoro-7 alpha -(Q)-estra-1,3,5(10)-triene-3,17 beta -diol; Q = 5-(N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino)-pentyl; 5-(2-(4,4,5,5,5-pentafluoropenylthiomethyl)-pyrrolidin-1-yl)-pentyl; 6-(N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino)-hexyl; 5-((2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl)-pentyl; 5-((2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl)-pen tyl; 5-((2S)-2-(4,4,5,5,5-pentafluoropentanesulfinylmethyl)-pyrrolidin-1-yl )-pentyl; or 5-((2S)-2-(4,4,5,5,5-pentafluoropentanesulfonylmethyl)-pyrrolidin-1-yl )-pentyl.